Sansalvamide A is produced by a marine fungus of the genus Fusarium found on Little San Salvador Island, Bahamas. It was isolated as reported in the literature (Fenical et al., Tetrahedron Lett. 1999, 40, 2913-16) and shown to have cytotoxic activity against several cancer cell lines. A study of the mechanism of action of this natural product in the poxvirus molluscum contagiosum virus showed it to be an inhibitor of topoisomerase I.
Notwithstanding the promise of sansalvamide A, many cancer disease states remain without an effective chemotherapy. For instance, most patients with pancreatic cancer die within six months of diagnosis: mortality and incidence are almost equal. Pancreatic cancer has recently overtaken prostate cancer as the third leading cause of cancer death in men (after lung and colon). It is also the fourth leading cause of cancer death in women (after lung, breast, and colon). Less than 20% of patients are diagnosed early enough in the disease process for potentially curative surgery. Even in these patients, however, the survival rate is still low. Gemcitabine is currently the first-line chemotherapeutic agent used in patients with pancreatic cancer, but it has little impact on survival.
Sansalvamide A is a cyclic depsipeptide with lipophilic properties affording it protease resistance and membrane permeability, allowing for greater oral bioavailability. The core ring structure restricts bond rotation and creates a more rigid conformation that results in a higher binding affinity and longer half-life in vivo. However, as shown below, sansalvamide A is somewhat limited in its potency. The search for an effective antitumor agent, for pancreatic and other cancer disease states, remains an on-going concern in the art.